A synthesis of diastereoisomeric pure reduced folates, as well as their importance in the pharmaceutical field, are described in European Patent Application No. 91 905 831.32101, publication No. 0 471 820.
In European Patent Application No. 91 121 326.2, publication No. 0 495 204 A1, there is described, among other things, a process for the preparation of (6S)- and (6R)-tetrahydrofolic acids using fractional crystallization of their corresponding acid addition salts with a sulfonic acid or with sulfuric acid. There is no disclosure of a direct, selective crystallization of (6S)-THF in the form of the free acid.
It is believed that the process described in EP 0 495 204 A1 contains certain unnecessary steps, such as the preparation of the acid addition salts and their transformation into free acids. For example, according to the embodiments described in the examples of the document, fractional crystallization of acid addition salts must always be carried out in the presence of an antioxidant, such as mercaptoethanol.
The process is not economical, and is detrimental to the environment. For example, at least one equivalent of a sulfonic acid salt or of a sulfuric acid salt is formed as by-product during liberation of the acid from the acid addition salt, which must be disposed of.
A direct, selective crystallization of (6S)-THF in the form of the free acid has not yet been described.